Proteins, as well as many other biologically active compounds, degrade over time in aqueous solution. Because of this chemical instability, protein solutions are often not suitable for use in drug delivery devices. Carriers, in which proteins do not dissolve but rather are suspended, can often offer improved chemical stability. Furthermore, it can be beneficial to suspend the beneficial agent in a carrier when the agent exhibits low solubility in the desired vehicle. However, suspensions can have poor physical stability due to settling and agglomeration of the suspended beneficial agent. The problems with non-aqueous carriers tend to be exacerbated as the concentration of the active compound is increased.
For drug delivering implants, dosing durations of up to one year are not unusual. Beneficial agents which have low therapeutic delivery rates are prime candidates for use in implants. When the device is implanted or stored, settling of the beneficial agent in the liquid formulation can occur. This heterogeneity can adversely effect the concentration of the beneficial agent dispensed. Compounding this problem is the size of the implanted beneficial agent reservoir. Implant reservoirs are generally on the order of 25-250 .mu.l. With this volume restriction, a formulation of high concentration (greater than or equal to 10%) and a minimum amount of suspension vehicle and other excipients is preferred.
Alpha interferon (.alpha.-IFN) is one example of a beneficial agent which provides a therapeutic effect at a low dose. This interferon is indicated in the treatment of chronic hepatitis because of its antiviral activity. Prescribed therapy presently entails injections of .alpha.-IFN solution, containing about 3.0.times.10.sup.6 IU (15 micrograms) of agent per dose, three times per week for a 4 to 6 month period. Frequent injections are required because of the short elimination half-life of .alpha.-IFN; most of the drug being completely cleared from the plasma within eight to ten hours after the injection.
U.S. Pat. Nos. 4,871,538 issued to Yim et al; 4,847,079 issued to Kwan et al; 5,081,156 issued to Yamashira et al, and European Publication No. 0,281,299 issued to Yim et al describe IFN/peptide compositions with concentrations between 10.sup.4 to 10.sup.8 IU/ml. In Kwan et al a pharmaceutical solution having a .alpha.-IFN concentration of 10.sup.3 to 10.sup.8 IU/ml is described. Yim describes a dosage range being between 10.sup.4 to 10.sup.8 IU .alpha.-IFN/ml. In Yim II, an insoluble complex including .alpha.-IFN, zinc, and protamine is suspended in a phosphate buffer. Yim I, Yim II, and Kuan, however, teach the use, in part, of an aqueous buffer in their compositions. This leads to possible hydrolysis of the compound, leading to chemical degradation and instability. Yamashira teaches a sustained release preparation of interferon in a n mixture with a biodegradable carrier. IFN is incorporated at concentrations of 10.sup.3 to 10.sup.8 IU per 1 mg of carrier or, alternatively, each dosage form containing 10.sup.4 to 10.sup.9 IU of interferon. Furthermore, while the patents and publications described above describe concentrations between 10.sup.4 to 10.sup.9 IU/ml, none describe concentrations on the order of 10.sup.9 to 10.sup.11 IU/ml.
There is a need for a novel composition comprising a nonaqueous suspension vehicle and concentrated protein/peptide as the beneficial agent for use in implanted, sustained release devices. While it is known in the art to achieve stable .alpha. IFN concentrations of up to 10.sup.8 IU/ml, this invention utilizes a novel combination whose combined effect produces a significant and surprising improvement in the physical and chemical stability of the beneficial agent compound over other formulations.